title: Synthesis of an esterase-sensitive cyclic prodrug of a model hexapeptide having enhanced membrane permeability and enzymatic stability using a 3-(2'-hydroxy-4',6'-dimethylphenyl)-3,3-dimethyl propionic Acid promoiety.
abstract: One of the major obstacles to the development of biologically active peptides as clinically useful therapeutic agents has been their low permeation through biological barriers (e.g., intestinal mucosa, blood-brain barrier) and their metabolic lability (1,2). Overcoming these problems is a very contemporary issue for the development of peptide pharmaceuticals. In the preceding chapter, we have indicated that masking the C- and N-terminal polar functional groups of a peptide through cyclization with an acyloxyalkoxy linker can greatly enhance the membrane permeation and metabolic stability of the linear peptide (3). In this chapter, we wish to report a method for the preparation of esterase-sensitive cyclic prodrugs of peptides by taking advantage of a unique "trimethyl lock"-facilitated lactonization system (Fig. 1). Substituted phenol propionic acid derivatives such as 2, upon unmasking of the hydroxyl group, undergo a facile spontaneous intramolecular cyclization to release the moieties attached to the carboxyl functional group (Fig. 1) (4-6). The facile cyclization reaction is the result of the "trimethyl lock", which was shown earlier to increase the rate of the cyclization reaction in the order of 10(5-7) (4-7). The result of such facilitation is that compound 2 has a half-life of only approximately 100 s at room temperature in aqueous solution (8,9). Such systems have been used to develop prodrugs of amines and alcohols (8-10) and redox-sensitive protecting groups of amines (11). Fig. 1. The design of an esterase sensitive prodrug system for the cyclic deriva-tization of peptides.
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS.
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.forename: S
authors.initials: S
authors.lastname: Gangwar
authors.forename: G
authors.initials: G
authors.lastname: Pauletti
authors.forename: T
authors.initials: T
authors.lastname: Siahaan
authors.forename: R T
authors.initials: RT
authors.lastname: Borchardt